DESCRIPTION: (Applicant's Description) To target vulnerable youths for intervention and prevention efforts, it is critical to identify biobehavioral factors that distinguish adolescents at increased risk for progressing to nicotine dependence. One factor shown to be associated with nicotine dependence in humans is dysregulation of the hypothalamic pituitary- adrenocortical (I-IPA) stress axis. However, it is unclear whether this dysregulation results from chronic nicotine use, or whether it precedes use and might distinguish those at increased risk for progressing to dependence. In laboratory animals, dysregulation of the adrenocortical stress hormones has been shown to both precede psychostimulant use and to distinguish animals with a greater propensity for psychostimulant self-administration. Animals who demonstrated greater reactivity to stress showed increased propensity for self-administration of various psychostimulants. Yet, the relationship between stress reactivity and increased risk for drug dependence has never been tested in humans or with nicotine. The proposed pilot study will investigate differences in adrenocortical reactivity between adolescents at greater and lesser risk for progression to nicotine dependence. Specifically, as prenatal nicotine exposure has been associated with increased risk for progression to nicotine dependence, we will examine the relationship between HPA stress reactivity and maternal smoking during pregnancy. Three groups of twenty same-sex adolescent sibling pairs will be recruited for the study including a) sibling pairs concordant for maternal smoking during pregnancy (MS-H-), h) pairs discordant only for maternal smoking during pregnancy (MS+-), and e) matched control pairs with no maternal history (MS--)of smoking. Groups will be compared on adrenocortical reactivity to a series of laboratory stressors. We hypothesize that the MS++ sibling pairs will show greater adrenocortical stress reactivity than the MS+- sibling pairs, who will show greater reactivity than the M-- pairs. Moreover, MS+ siblings from the MS+- pairs will show similar reactivity to the MS++ pairs and greater reactivity than the MS-siblings from the MS+- pairs, who will show reactivity similar to the MS-- pairs. Results will represent a first step toward characterizing a biobehavioral marker for nicotine dependence and may elucidate mechanisms underlying the effects of maternal smoking during pregnancy. Results may also lead to longitudinal marker studies with implications for genetic mechanisms as well as targeted intervention and prevention efforts.